GABAergic interneurons perform crucial roles in cerebral cortical development and function, but little is known about the molecular mechanisms that control interneuron fate determination. Most cortical interneurons originate in the medial ganglionic eminence (MGE) of the ventral forebrain, where recent evidence has begun to further define the origins of distinct subgroups of cortical interneurons (Xu...Anderson, 2004). The experiments described below are designed to examine how molecular signals specify interneurons within the MGE. To achieve this goal we will use a combination of in vivo and in vitro gain and loss of function studies focused on four proteins: 1) Sonic Hedgehog (Shh), a morphogen that promotes ventral neural tube development including the MGE, 2) NKX2.1, a transcription factor target of Shh signaling that is required for normal MGE development, 3) LHX6, a transcription factor that is, downstream of Nkx2.1 in the MGE and is expressed in interneurons migrating to the cerebral cortex, 4) ARX1, also expressed in migrating interneurons, and required for normal interneuron development. Since mutations inShh, Nkx2.1 and Arx1 have been linked to developmental forebrain abnormalities in humans, these studies lay the groundwork for identifying the "molecular code" for interneuron specification that will enhance our understanding of and treatment approaches for a variety of neuropathologic conditions. In addition, these studies are highly synergistic with other aims of the PPG including;the molecular control of cortical and subcortical proliferation by cyclin D2 and Shh (Projects 1 and 3), the role of migratory subcortical interneurons in cortical proliferation (Project 3) and the histological, physiological and behavioral effects of altered interneuron output by the MGE (Projects 1 and 4). In sum, the overarching goal of this project is to link clinically relevant alterations in embryonic forebrain development with postnatal histological and functional phenotypes.